Dasotraline [(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetra-hydronaphthalene-1-amine] is a dopamine and norepinephrine reuptake inhibitor with weak serotonin reuptake inhibition:
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DAT: IC50 = 3 nM
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NET: IC50 = 4 nM
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SERT: IC50 = 15 nM
Tetrodotoxin blocked neuronal firing and abolished the ability of dasotralin to increase synaptic monoamine concentrations, demonstrating that dasotralin is a reuptake inhibitor and not a monoamine releaser.
Dasotraline has been studied in relation to its use in ADHD
Sunuvion is said to have discontinued development of dasotralin in the meantime.
Orally ingested dasotraline is slowly absorbed in humans, with a tmax of 10-12 hours and a very long terminal elimination half-life of 47-77 hours. Dasotraline may have a sustained treatment benefit in ADHD due to its stable plasma concentration over 24 hours when administered once daily while having a low potential for abuse. Dasotraline thus differs markedly from the rapid, large, and short-lived increase in dopamine efflux of d-amphetamine and MPH.
In a placebo-controlled double-blind study, a single daily dose of 8 mg dasotraline (but not 4 mg dasotraline) showed significant improvement in ADHD-HI Rating Scale (ADHD-HI) symptoms and CGI-S scores at 4 weeks compared with placebo.
At 4 mg, a good 10% of subjects terminated the study prematurely, at 8 mg just under 28%. This appears to be quite high.
The high insomnia could result from the long half-life of 47 hours, which, on the other hand, would allow a single daily dose leading to a constant plasma level after 10 days of ingestion.
On the other hand, insomnia was not a predictor of dropout from study participation.
Another 6-week RCT of 342 children aged 6-12 years found significantly better improvement in ADHD symptoms with 4 mg/day than placebo, with an effect size of 0.48. 2 mg/day showed no improvement
Discontinuation rates due to adverse events were 12.2% (4 mg/day), 6.3% (2 mg/day), and 1.7% (placebo), respectively.
Side effects in the studies were mainly (compared to placebo):
- Sleep problems
- These are likely to result from the long half-life
- Dry mouth
- Nausea
- Postural orthostatic tachycardia syndrome (5.4% vs. 0%)
- Perceptual disorders (5.4% vs. 0%)
- Decreased appetite (10.7% vs. 3.6%)
- Weight loss
- Irritability (5.4% vs. 3.6%)
- Headache (10.7% vs. 8.9%)
- Affect lability (8.9% vs. 7.1%)
A study in adults with 6 mg/day found only partially significant improvements in ADHD symptomatology over placebo, but a trend toward improvement. This was due to a surprisingly large improvement in the placebo group
No serious side effects or clinically relevant changes in blood pressure or heart rate were found.
